Deposition of amyloid in the cerebral cortex of humans may be one of several key early events in the pathogenesis of Alzheimer's disease (AD), but the etiology of this process remains unknown. Evidence for a mutation in the gene for the amyloid precursor protein (APP) exists indicating a genetic mechanism may cause AD in some families. AD could also be caused by the release of beta A4 amyloid in the brain following severe head injury. Thus, as might be expected, the etiology of AD (and extensive beta amyloid deposition in the cerebrum) is multifactorial and likely the result of factors both genetic and not genetic. We intend to exploit and extend these concepts by proposing that the cause (or causes) of AD may be the result of an interaction between genetic and environmental factors. The hypothesis tested in this LEAD award is twofold: familial AD is a complex genetic disorder in which reduced penetrance results from either the exposure to, or the lack of exposure to, environmental factors and nonfamilial AD results from environmental factors or previously unexplored genetic mechanisms such as mitotic nondisjunction leading to low level mosaicism for trisomy 21. In Project 1, we will identify and measure the relationship between specific environmental and genetic risk factors in AD, and identify mutations in the coding region and upstream promoter sequences of the APP gene or the occurrence of low level mosaicism for trisomy 21 in patients and controls from 3 ethnic groups (Black, Hispanic and White) in a heterogeneous community in northern Manhattan. In Project 2, similar interviews, clinical and laboratory examinations will be done in all living first-degree relatives of all patients with familial AD and a sample of those with "sporadic" AD (identified in Project 1) in order to establish age-specific risk of AD, and associations of AD with environmental risk factors and with mutations in the coding region and upstream promoter sequences of the APP gene. In Project 3, a prospective case-base study we will determine the cumulative incidence of AD in those exposed and unexposed to the risk factors identified in Project 1, compare rates across ethnic groups; determine for each risk factor the attributable risk and relative risks and establish risk profiles. Our results will provide methods to predict the risk of AD in 3 distinct ethnic groups represented in our community according to the presence or absence of certain risk factors of genetic susceptibility.